Metabolic Syndrome

In humans, developing metabolic disease, particularly type 2 diabetes, is correlated with having bacteria that penetrate the mucus lining of the colon, according to a study led by Drs. Benoit Chassaing and Andrew Gewirtz at Georgia State University.

The findings, which provide insight on how people develop insulin resistance-associated dysglycemia (abnormal blood glucose levels), are published in the journal Cellular and Molecular Gastroenterology and Hepatology.

Metabolic syndrome is the term for a group of factors that raise a person’s risk for heart disease and other health problems, such as diabetes and stroke. Such risk factors include a large waistline, a high triglyceride level (type of fat found in the blood), low HDL cholesterol level, high blood pressure and high fasting blood sugar levels. Metabolic syndrome, which has become far more common due to a rise in obesity rates among adults, is a leading risk factor for many serious, life-threatening diseases, including type 2 diabetes and heart disease, according to the National Institutes of Health.

“Alterations in bacteria have been associated with metabolic diseases, including obesity and type 2 diabetes, but mechanisms remain elusive,” said Gewirtz, professor in the Institute for Biomedical Sciences at Georgia State.

“Previous studies in mice have indicated that bacteria that are able to encroach upon the epithelium might be able to promote inflammation that drives metabolic diseases, and now we’ve shown that this is also a feature of metabolic disease in humans, specifically type 2 diabetics who are exhibiting microbiota encroachment.”

The epithelium is the mucus-lined cellular covering of internal and external surfaces of the body, including the intestinal tract. Gut microbiota is the collective term for the communities of microscopic living organisms that inhabit this environment. Gut microbiota that live in the outer regions of the mucus and remain a safe distance from epithelial cells provide a benefit to the host, but Chassaing and Gewirtz hypothesise that microbiota that encroach upon host cells drive chronic inflammation that interferes with the normal action of insulin, promoting type 2 diabetes.

In this study, the researchers used samples from human subjects enrolled at the Veteran’s Administration Hospital in Atlanta. The subjects, at least 21 years old with no major health problems besides diabetes, were undergoing colonoscopy for colon cancer screening. The researchers obtained each subject’s history of diabetes and gastrointestinal complaints through interviews and reviewing medical records. During the colonoscopy procedure, two mucosal biopsies were taken from the left colon and analysed.

“The data are impressive and may have opened a new field of investigation in metabolic function and type 2 diabetes,” said Dr. Samuel Klein, chief of the Division of Geriatrics and Nutritional Science at the Washington University School of Medicine Diabetes Research Center.

The researchers are conducting follow-up studies to determine the identity of the bacteria that are invading the colon lining and are exploring remedies to prevent such bacteria encroachment.

Chassaing, assistant professor in the Institute for Biomedical Sciences and Center for Inflammation, Immunity and Infection, is lead author of the study.

Co-authors of the paper include Dr. Shreya M. Raja and Dr. Shanthi Srinivasan of Emory University School of Medicine and Dr. James D. Lewis of Perelman School of Medicine at University of Pennsylvania.

The study is funded by the National Institutes of Health and the Crohn’s and Colitis Foundation.

More About Metabolic Syndrome.

A rise in caloric consumption combined with a decrease in physical activity has contributed to a boom of metabolic diseases, such as type 2 diabetes mellitus and cardiovascular diseases (e.g., heart failure and stroke). Over the last couple of decades, studies exploring these diseases have uncovered some of the complex pathophysiological mechanisms involved, resulting in the identification of a plethora of interconnected physiological, pathophysiological, biochemical, and clinical factors that play a role in their development. These factors include obesity/abdominal adiposity, insulin resistance, dyslipidemia, a low-grade state of chronic inflammation, hypoxia, oxidative stress, fasting hyperglycemia, high blood pressure (hypertension), endothelial dysfunction, a hyper-coagulable state, genetics, and more. This constellation of interconnected risk factors that play a role in the development of metabolic and cardiovascular diseases has been dubbed metabolic syndrome.

The concept of this complex syndrome was first introduced by Gerald M. Raven during the Banting Medal Address during the 1988 American Diabetes Association meeting. He proposed that cardiovascular risk was high among insulin-resistant, hyper-insulinemic individuals who were glucose intolerant and who exhibited a collection of other risk factors, such as increased levels of plasma triglyceride, low HDL-cholesterol, and essential hypertension. He called the collection of these factors Syndrome X, as the significance of these abnormalities and their precise role in cardiovascular diseases was not fully understood at the time. While the condition has been given several definitions over the years based on improved understanding, a harmonized definition for metabolic syndrome was the result of a 2009 joint meeting of the American Heart Association, the National Heart Lung and Blood Institute, the International Diabetes Foundation, the World Heart Federation and the International Association for the Study of Obesity. Accordingly, metabolic syndrome is diagnosed based on the presence of any three of five criteria:

• Increased waist circumference (as a measure of abdominal obesity that is specific to populations and ethnic groups);

• Triglycerides levels at 150mg/dl or higher;

• HDL-c levels at 40 mg/dL or lower in men and 50 mg/dL or lower in women;

• Blood pressure at 130/85 or higher; and

• Fasting plasma glucose (glycemia) at 100mg/dL or higher.

Diagnosed with these criteria, metabolic syndrome confers a five-fold increased risk for type 2 diabetes and a three-fold increased risk for cardiovascular disease, including an up to four-fold increased risk for stroke or heart failure. Metabolic syndrome also is associated with several other diseases, including many cancers, polycystic ovarian syndrome, and neurological disorders.

With approximately 35% of all adults and 50% of individuals aged 60 years or older estimated to have metabolic syndrome, it is a major public health issue and is changing what was thought of as a “normal” individual. The presence of metabolic syndrome in an increasing percentage of individuals suggests an altered metabolic, physiological, and pathophysiological state that may change or exacerbate the toxic responses to drugs and/or environmental toxicants. And this syndrome is not limited to the adult population. It increasingly is diagnosed in the paediatric population with a prevalence rate of about 11.9% in overweight children and 29% in obese children.

While several intricate pathways and mechanisms are at play in metabolic syndrome, obesity (abdominal obesity in particular) and insulin resistance are considered to be at the core of this syndrome. For example, a positive energy balance leads to adipose tissue expansion and obesity resulting in consequences, which include the following:

• Infiltration of macrophages and other immune cells into the adipose tissue, giving rise to an inflamed adipose tissue with an increased secretion of pro-inflammatory cytokines and adipokines and a concomitant decrease in the anti-inflammatory adipokine, adiponectin.

• Ectopic deposition of fat in key organs such as the liver, heart, skeletal muscle, and pancreas due to spill over from expanded adipose tissue, resulting in tissue lipotoxicity and consequent inhibition of insulin signaling.

• Binding of circulating free fatty acids to toll receptors on various organs, augmenting inflammatory signaling via the downstream activation of NFκB and JNK pathways resulting in a vicious cycle of inflammation, which further inhibits insulin signaling in these tissues.

• Free fatty acid accumulation in tissues and in its breakdown to intracellular diacylglycerol and ceramide, which interferes with insulin signaling and insulin-stimulated glucose uptake. This accumulation of free fatty acids and its incomplete oxidation mediates mitochondrial dysfunction, which triggers formation of reactive oxygen species that induce oxidative stress, which further impairs mitochondrial function. Increased reactive oxygen species levels also hinder insulin signaling and impair GLUT4 translocation.

A failure of cells to respond to insulin results in the pathological condition of insulin resistance. Insulin, by activating complex signaling pathways involving pI3K/AKT, MAPK, and clb and by binding to transcriptions factors such as FOXO and PPARg, regulates glucose uptake and glucose and lipid metabolism in peripheral tissues. Insulin resistance disrupts these pathways, resulting in hyperglycemia and dyslipidemia. Dyslipidemia also results from the accumulation of free fatty acids in the liver along with insulin-augmented lipogenesis, increasing triglyceride production and release, together with an increased hepatic uptake and renal clearance of HDL-c resulting in a dysregulated lipid profile of low levels of HDL-c and high triglyceride seen in metabolic syndrome. Glucotoxicity and lipotoxicity mediate pancreatic β-cell dysfunction in insulin resistance and hyperinsulinemia. This combination of insulin resistance and hyperinsulinemia, additionally, plays a role in the development of hypertension by tipping the balance between endothelial cell secretion of the vasodilator, NO, and the vasoconstrictor, ET-1.

Although obesity and IR are at the core of the pathophysiological mechanisms of metabolic syndrome, several other factors also are implicated, including dysregulation of the hypothalamic-pituitary-adrenal axis, the renin-angiotensin-aldosterone system, the autonomic nervous system, impact of gut microbiome on metabolism, the cellular and metabolic alterations in response to drugs, alcohol, and environmental toxicants. Both genetic and epigenetic mechanisms are thought to play a role besides environmental and lifestyle causes of MS.

An examination of the metabolic disturbances associated with metabolic syndrome reveals that many of the pathways and mechanisms involved overlap with those affected by drugs and environmental toxicants and can result in similar types of cellular and organ toxicities. It also is conceivable that drug responses and toxicities may be altered in subjects with metabolic syndrome in whom several metabolic and signaling pathways have gone awry.